Will DAPA-HF Turn the Tide on Heart Failure?

John M. Mandrola, MD


September 06, 2019

When Professor John McMurray from the University of Glasgow presented the decidedly positive results of the Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction (DAPA-HF) trial[1,2] at the European Society of Cardiology (ESC) Congress in Paris, it felt like a before-and-after moment in medical history.

By now, most readers know that the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin added to guideline-directed medical therapy (GDMT)  in more than 4700 patients with heart failure with reduced ejection fraction (HFrEF) was associated with a 26% reduction in death due to cardiovascular (CV) causes, heart failure hospitalizations, and urgent heart failure visits compared with GDMT alone (hazard ratio [HR], 0.74 [95% confidence interval (CI), 0.65 - 0.85]; P = .00001).

Crucially, DAPA-HF was a heart failure trial; more than half the patients did not have diabetes. Journalist Patrice Wendling has excellent coverage of the trial:

Here are some key points from the presentation and trial discussant:

  • Both components of the primary endpoint were significantly reduced: CV death by 18% and any worsening heart failure event by 30%.

  • The Kaplan-Meier curves for heart failure endpoints separated within months, suggesting an early benefit of dapagliflozin, likely via its diuretic effect.

  • The benefit was consistent across most subgroups, notably those with and without diabetes and those on or off angiotensin-neprilysin inhibitors (ARNIs).

  • All-cause mortality was reduced (HR, 0.83 [95% CI, 0.71 - 0.97]).

  • The degree of risk reduction was similar to that seen in recent heart failure trials, including PARADIGM-HF[3] (sacubitril/valsartan), EMPHASIS-HF[4] (eplerenone), and SHIFT[5] (ivabradine).

  • Adverse events overall were similar. 


Start with caution: We don't have the full paper. Professor McMurray himself reiterated the preliminary nature of these findings by saying that he absolutely would not prescribe these drugs (now) in nondiabetic patients with heart failure because the results need to be reviewed by regulators and the guideline writers.

Here is how Sanjay Kaul, MD, from Cedars Sinai in Los Angeles, California, described the findings  to me via email: "Decent result; CV death risk reduction is not very robust; all-cause death risk reduction cannot be claimed because of statistical rules of engagement, but otherwise the benefit-risk is highly desirable."

Since I have no experience with SGLT2 inhibitors (yet), I reached out to other experts. Modifiers such as "amazing" and "spectacular" were used in many of their replies.

Ethan Weiss, MD, from the University of California San Francisco, wrote, "If you had proposed this as an idea to me years ago, I would have said it is terrible and, frankly, as diabetes meds, [SGLT2 inhibitors] are not great."

Weiss also noted the serendipity of this discovery. Without the controversy over rosiglitazone, which prompted the US Food and Drug Administration to require CV safety trials for all diabetes meds, there may not have been an EMPA-REG trial,[6] which found that the SGLT2 inhibitor empagliflozin reduced cardiac outcomes in patients with diabetes.

Nephrologist Swapnil Hiremath from the University of Ottawa, Ontario, Canada, called the antihyperglycemic effect of SGLT2 inhibition just an interesting side effect and wrote that these drugs should be prescribed by everyone. He also pointed me to favorable data with the SGLT2 inhibitors in high-CV-risk patients with diabetes dating back to 2014.[7,8]

The prolific educator Joel Topf, MD from St Clair Nephrology, Detroit, sent me a slide showing similar CV risk reductions for simvastatin in secondary prevention[9] and empagliflozin in EMPA-REG. He, too, believes that this class of drugs is rewriting the rules of cardiology and nephrology. 

Three Challenges

Almost everyone I spoke with mentioned the impending learning curve. Hiremath called SGLT2 inhibitors potent drugs with potent side effects. "We will see more mycotic infections (from the glucosuria), and more euglycemic diabetic ketoacidosis."[10]

Another issue is pill burden. GDMT for HFrEF includes three classes of drugs, and more than 90% of patients in DAPA-HF also took diuretics. These are just the cardiac meds. Many patients with heart failure have comorbidities. Although the mean age of patients in the trial was 66 years, once these drugs are approved, marketed, and codified as "GDMT" in quality measures, clinicians will surely prescribe them for older patients with multiple conditions. How these drugs perform in the real world will be an important area of future study.

Then there are the costs. In an email, Cait O'Sullivan, an academic PharmD at the Therapeutics Initiative in British Columbia, Canada, wrote that dapagliflozin costs approximately $1000 Canadian dollars per year. US costs will be many multiples of that. The novelty of this class of drug accentuates the cost issue. ARNI drugs are costly, but clinicians can still inhibit the renin-angiotensin system with a less expensive angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. We won't have this choice with SGLT2 inhibitors.


Knowing my caution in embracing novel therapies, Hiremath admonished me that for these drugs, he would be an early adopter, not a medical conservative.

The medical conservative, however, adopts new therapies when the benefit is clear and the evidence strong and unbiased.[11] The initial look at DAPA-HF fits these criteria.

More good news is that we will not have to rely on one trial or wait long. An ongoing trial on empagliflozin heart failure finishes soon.

My favorite part of the SGLT2 inhibitor story is how it shows the changing nature of medical practice. Not long ago, SGLT2 inhibitors for heart failure hadn't even been thought of. If other trials confirm these results, we will have to go back to school.

When I started cardiology, systolic heart failure was a death sentence. Now look, it’s almost a stable chronic condition. That is neat.

The commentators have disclosed no relevant financial relationships.


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